Neurodegenerative disorders with prominent brain alpha-synuclein filamentous aggregates in neurons or glia are known as "synucleinopathies". Common synucleinopathies characterized by neuronal alpha-synuclein inclusions, known as Lewy bodies (Lbs), include Parkinson's disease (PD) and dementia with Lbs (DLB). Multiple system atrophy (MSA) is characterized by numerous glial cell inclusions (GCIs) and the less frequent neuronal cell inclusions (NCIs), both compromised of alpha-synuclein. The majority of PD is sporadic but two mutations have been identified in the alpha-synuclein gene of rare kindreds with an autosomal dominant form of hereditary PD. Thus, filamentous alpha-synuclein inclusions may play a role in the onset or progression of synucleinopathies. To test the hypothesis that alpha- synuclein abnormalities are implicated in mechanisms of brain degeneration in PD and related synucleinopathies, we will produce and analyze transgenic mice that over-express wildtype or mutant human alpha-synuclein in neurons or glia. We will assess the biological and pathological consequences of alpha-synuclein over-expression and evaluate the effects of the mutations on the pathogenesis of synucleinopathies in transgenic mice. The properties of intracellular alpha-synuclein inclusions that may develop in these transgenic animals will be characterized and compared to authentic Lbs and GCIs in human synucleinopathies. Finally, we will use the alpha-synuclein transgenic mouse models and primary neuronal cultures derived from these mice to address important questions on mechanisms leading to alpha-synuclein pathologies and their contribution to brain degeneration in synucleinopathies.